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1.
Cancer Cell Int ; 21(1): 381, 2021 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-34273970

RESUMEN

BACKGROUND: Osteosarcoma was the most common primary bone malignancy in children and adolescents. It was imperative to identify effective prognostic biomarkers for this cancer. This study was aimed to identify potential crucial genes of osteosarcoma by integrated bioinformatics analysis. METHODS: Identification of differentially expressed genes from public data gene expression profiles (GSE42352), functional and pathway enrichment analysis, protein-protein interaction (PPI) network construction and module analysis, Cox regression and survival analysis was conducted. RESULTS: Totally 17 co-differential genes were found to be differentially expressed. These genes were enriched in biological processes, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) pathway of inflammatory immune response. PPI network was constructed with 63 differentially expressed genes that co-existed between the test set and the validation set. The area under the receiver operating characteristic curve (AUC value) was 0.855, which indicated that the expression of PODN had a good diagnostic value for osteosarcoma. Furthermore, Cox regression and survival analysis revealed 5 genes were statistically significant. CONCLUSIONS: PODN was regarded as a potential biomarker for the diagnosis and prognosis of osteosarcoma, ACTA2, COL6A1, FAP, OLFML2B and COL6A3, can be used as potential prognostic indicators for osteosarcoma.

2.
Int J Med Sci ; 18(9): 1999-2007, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33850470

RESUMEN

Precartilaginous stem cells (PCSCs) are able to initiate chondrocyte and bone development. The present study aimed to investigate the role of miR-143 and the underlying mechanisms involved in PCSC proliferation. In a rat growth plate injury model, tissue from the injury site was collected and the expression of miR-143 and its potential targets was determined. PCSCs were isolated from the rabbits' distal epiphyseal growth plate. Cell viability, DNA synthesis, and apoptosis were determined with MTT, BrdU, and flow cytometric analysis, respectively. Real time PCR and western blot were performed to detect the mRNA and protein expression of the indicated genes. Indian hedgehog (IHH) was identified as a target gene for miR-143 with luciferase reporter assay. Decreased expression of miR-143 and increased expression of IHH gene were observed in the growth plate after injury. miR-143 mimics decreased cell viability and DNA synthesis and promoted apoptosis of PCSCs. Conversely, siRNA-mediated inhibition of miR-143 led to increased growth and suppressed apoptosis of PCSCs. Transfection of miR-143 decreased luciferase activity of wild-type IHH but had no effect when the 3'-UTR of IHH was mutated. Furthermore, the effect of miR-143 overexpression was neutralized by overexpression of IHH. Our study showed that miR-143 is involved in growth plate behavior and regulates PCSC growth by targeting IHH, suggesting that miR-143 may serve as a novel target for PCSC-related diseases.


Asunto(s)
Placa de Crecimiento/patología , Proteínas Hedgehog/genética , MicroARNs/metabolismo , Fracturas de Salter-Harris/patología , Células Madre/metabolismo , Animales , Apoptosis/genética , Proliferación Celular/genética , Células Cultivadas , Modelos Animales de Enfermedad , Placa de Crecimiento/citología , Placa de Crecimiento/crecimiento & desarrollo , Humanos , Cultivo Primario de Células , Conejos , Ratas , Fracturas de Salter-Harris/terapia , Trasplante de Células Madre
3.
Biosci Rep ; 40(5)2020 05 29.
Artículo en Inglés | MEDLINE | ID: mdl-32319512

RESUMEN

Precartilaginous stem cells (PCSCs) are adult stem cells that can initiate chondrocytes and bone development. In the present study, we explored whether miR-132/212 was involved in the proliferation of PCSCs via Hedgehog signaling pathway. PCSCs were isolated and purified with the fibroblast growth factor receptor-3 (FGFR-3) antibody. Cell viability, DNA synthesis and apoptosis were measured using MTT, BrdU and flow cytometric analysis. The mRNA and protein expression were detected by real-time PCR and Western blot, respectively. The target gene for miR-132/212 was validated by luciferase reporter assay. Results showed that transfection with miR-132/212 mimic significantly increased cell viability and DNA synthesis, and inhibited apoptosis of PCSCs. By contrast, miR-132/212 inhibitor could suppress growth and promote apoptosis of PCSCs. Luciferase reporter assays indicated that transfection of miR-132/212 led to a marked reduction of luciferase activity, but had no effect on PTCH1 3'-UTR mutated fragment, suggesting that Patched1 (PTCH1) is a target of miR-132/212. Furthermore, treatment with miR-132/212 mimics obviously increased the protein expression of Indian hedgehog (Ihh) and parathyroid hormone related protein (PTHrP), which was decreased after treatment with Hedgehog signaling inhibitor, cyclopamine. We also found that inhibition of Ihh/PTHrP signaling by cyclopamine significantly suppressed growth and DNA synthesis, and induced apoptosis in PCSCs. These findings demonstrate that miR-132/212 promotes growth and inhibits apoptosis in PCSCs by regulating PTCH1-mediated Ihh/PTHrP pathway, suggesting that miR-132/212 cluster might serve as a novel target for bone diseases.


Asunto(s)
Células Madre Adultas/fisiología , Proliferación Celular/genética , Condrocitos/fisiología , MicroARNs/metabolismo , Animales , Apoptosis/efectos de los fármacos , Cartílago Articular/citología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Proteínas Hedgehog/antagonistas & inhibidores , Proteínas Hedgehog/metabolismo , Familia de Multigenes , Proteína Relacionada con la Hormona Paratiroidea/metabolismo , Receptor Patched-1/metabolismo , Cultivo Primario de Células , Conejos , Alcaloides de Veratrum/farmacología
4.
Genomics ; 111(3): 320-326, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-29486210

RESUMEN

Developmental dysplasia of the hip (DDH) is a common congenital malformation characterized by mismatch in shape between the femoral head and acetabulum, and leads to hip dysplasia. To date, the pathogenesis of DDH is poorly understood and may involve multiple factors, including genetic predisposition. However, comprehensive genetic analysis has not been applied to investigate a genetic component of DDH. In the present study, 10 pairs of healthy fathers and DDH daughters were enrolled to identify genetic hallmarks of DDH using high throughput whole genome sequencing. The DDH-specific DNA mutations were found in each patient. Overall 1344 genes contained DDH-specific mutations. Functional enrichment analysis showed that these genes played important roles in the cytoskeleton, microtubule cytoskeleton, sarcoplasm and microtubule associated complex. These functions affected osteoblast and osteoclast development. Therefore, we proposed that the DDH-specific mutations might affect bone development, and caused DDH. Our pairwise high throughput sequencing results comprehensively delineated genetic hallmarks of DDH. Further research into the biological impact of these mutations may inform the development of DDH diagnostic tools and allow neonatal gene screening.


Asunto(s)
Luxación Congénita de la Cadera/genética , Mutación , Adulto , Preescolar , Femenino , Luxación Congénita de la Cadera/patología , Humanos , Lactante , Masculino , Osteogénesis/genética , Linaje , Secuenciación Completa del Genoma
5.
Int J Nanomedicine ; 12: 4225-4239, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28652729

RESUMEN

To design a rapid release liposomal system for cancer therapy, a NIR responsive bubble-generating thermosensitive liposome (BTSL) system combined with photothermal agent (Cypate), doxorubicin (DOX), and NH4HCO3 was developed. Cypate/DOX-BTSL exhibited a good aqueous stability, photostability, and photothermal effect. In vitro release suggested that the amounts of DOX released from BTSL were obviously higher than that of (NH4)2SO4 liposomes at 42°C. After NIR irradiation, the hyperthermic temperature induced by Cypate led to the decomposition of NH4HCO3 and the generation of a large number of CO2 bubbles, triggering a rapid release of drugs. Confocal laser scanning microscope and acridine orange staining indicated that Cypate/DOX-BTSL upon irradiation could facilitate to disrupt the lysosomal membranes and realize endolysosomal escape into cytosol, improving the intracellular uptake of DOX clearly. MTT and trypan blue staining implied that the cell damage of Cypate/DOX-BTSL with NIR irradiation was more severe than that in the groups without irradiation. In vivo results indicated that Cypate/DOX-BTSL with irradiation could dramatically increase the accumulation of DOX in tumor, inhibit tumor growth, and reduce systemic side effects of DOX. These data demonstrated that Cypate/DOX-BTSL has the potential to be used as a NIR responsive liposomal system for a rapid release of drugs in thermochemotherapy.


Asunto(s)
Antineoplásicos/administración & dosificación , Doxorrubicina/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Hipertermia Inducida/métodos , Liposomas/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Bicarbonatos/química , Bicarbonatos/farmacocinética , Línea Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacocinética , Liberación de Fármacos , Femenino , Humanos , Indoles/química , Células MCF-7 , Ratones Endogámicos BALB C , Propionatos/química , Temperatura , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Oncotarget ; 7(19): 27422-9, 2016 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-27027431

RESUMEN

p21 protein (Cdc42/Rac)-activated kinase 1 (PAK1) expression appears to be predictive of prognosis in various solid tumors, though the evidence is not yet conclusive. We therefore performed a meta-analysis to explore the relationship between PAK1 and prognosis in patients with solid tumors. Relevant publications were searched in several widely used databases, and 15 studies (3068 patients) were included in the meta-analysis. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between PAK1 and prognosis. Associations between PAK1 expression and prognosis were observed for overall survival (HR = 2.81, 95% CI = 1.07-7.39) and disease-specific survival (HR = 2.15, 95% CI = 1.47-3.16). No such association was detected for time to tumor progression (HR = 1.78, 95% CI = 0.99-3.21).Our meta-analysis thus indicates that PAK1 expression may be a predictive marker of overall survival and disease-specific survival in patients with solid tumors.


Asunto(s)
Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Neoplasias/genética , Quinasas p21 Activadas/genética , Biomarcadores de Tumor/genética , Supervivencia sin Enfermedad , Humanos , Neoplasias/enzimología , Neoplasias/patología , Pronóstico , Quinasas p21 Activadas/metabolismo
7.
J Exp Clin Cancer Res ; 34: 4, 2015 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-25609158

RESUMEN

BACKGROUND: Pediatric acute myeloid leukemia (AML) comprises up to 20% of all childhood leukemia. Recent research shows that aberrant DNA methylation patterning may play a role in leukemogenesis. The epigenetic silencing of the EBF3 locus is very frequent in glioblastoma. However, the expression profiles and molecular function of EBF3 in pediatric AML is still unclear. METHODS: Twelve human acute leukemia cell lines, 105 pediatric AML samples and 30 normal bone marrow/idiopathic thrombocytopenic purpura (NBM/ITP) control samples were analyzed. Transcriptional level of EBF3 was evaluated by semi-quantitative and real-time PCR. EBF3 methylation status was determined by methylation specific PCR (MSP) and bisulfite genomic sequencing (BGS). The molecular mechanism of EBF3 was investigated by apoptosis assays and PCR array analysis. RESULTS: EBF3 promoter was hypermethylated in 10/12 leukemia cell lines. Aberrant EBF3 methylation was observed in 42.9% (45/105) of the pediatric AML samples using MSP analysis, and the BGS results confirmed promoter methylation. EBF3 expression was decreased in the AML samples compared with control. Methylated samples revealed similar survival outcomes by Kaplan-Meier survival analysis. EBF3 overexpression significantly inhibited cell proliferation and increased apoptosis. Real-time PCR array analysis revealed 93 dysregulated genes possibly implicated in the apoptosis of EBF3-induced AML cells. CONCLUSION: In this study, we firstly identified epigenetic inactivation of EBF3 in both AML cell lines and pediatric AML samples for the first time. Our findings also showed for the first time that transcriptional overexpression of EBF3 could inhibit proliferation and induce apoptosis in AML cells. We identified 93 dysregulated apoptosis-related genes in EBF3-overexpressing, including DCC, AIFM2 and DAPK1. Most of these genes have never been related with EBF3 over expression. These results may provide new insights into the molecular mechanism of EBF3-induced apoptosis; however, further research will be required to determine the underlying details. Our findings suggest that EBF3 may act as a putative tumor suppressor gene in pediatric AML.


Asunto(s)
Metilación de ADN , Genes Supresores de Tumor , Leucemia Mieloide Aguda/genética , Regiones Promotoras Genéticas , Factores de Transcripción/genética , Adolescente , Factores de Edad , Apoptosis/genética , Línea Celular Tumoral , Niño , Preescolar , Análisis por Conglomerados , Epigénesis Genética , Femenino , Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica , Células HL-60 , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Masculino , Pronóstico , Transducción de Señal
8.
Int J Mol Sci ; 16(1): 1266-92, 2015 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-25574601

RESUMEN

Polo-like kinase 1 (PLK1) is highly expressed in many cancers and therefore a biomarker of transformation and potential target for the development of cancer-specific small molecule drugs. RO3280 was recently identified as a novel PLK1 inhibitor; however its therapeutic effects in leukemia treatment are still unknown. We found that the PLK1 protein was highly expressed in leukemia cell lines as well as 73.3% (11/15) of pediatric acute myeloid leukemia (AML) samples. PLK1 mRNA expression was significantly higher in AML samples compared with control samples (82.95 ± 110.28 vs. 6.36 ± 6.35; p < 0.001). Kaplan-Meier survival analysis revealed that shorter survival time correlated with high tumor PLK1 expression (p = 0.002). The 50% inhibitory concentration (IC50) of RO3280 for acute leukemia cells was between 74 and 797 nM. The IC50 of RO3280 in primary acute lymphocytic leukemia (ALL) and AML cells was between 35.49 and 110.76 nM and 52.80 and 147.50 nM, respectively. RO3280 induced apoptosis and cell cycle disorder in leukemia cells. RO3280 treatment regulated several apoptosis-associated genes. The regulation of DCC, CDKN1A, BTK, and SOCS2 was verified by western blot. These results provide insights into the potential use of RO3280 for AML therapy; however, the underlying mechanisms remain to be determined.


Asunto(s)
Apoptosis/efectos de los fármacos , Azepinas/toxicidad , Proteínas de Ciclo Celular/antagonistas & inhibidores , Leucemia Mieloide Aguda/patología , Inhibidores de Proteínas Quinasas/toxicidad , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Pirimidinas/toxicidad , Azepinas/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proteínas de Ciclo Celular/metabolismo , Niño , Preescolar , Análisis por Conglomerados , Fragmentación del ADN/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Femenino , Células HL-60 , Humanos , Células K562 , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidad , Masculino , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Pirimidinas/química , Células Tumorales Cultivadas , Regulación hacia Arriba/efectos de los fármacos , Quinasa Tipo Polo 1
9.
Int J Mol Med ; 34(6): 1505-15, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25319049

RESUMEN

Acute myeloid leukemia (AML) is the second-most common form of leukemia in children. Aberrant DNA methylation patterns are characteristic of AML. Zinc finger protein 382 (ZNF382) has been suggested to be a tumor suppressor gene possibly regulated by promoter hypermethylation in various types of human cancer. However, ZNF382 expression and methylation status in pediatric AML is unknown. In the present study, ZNF382 transcription levels were evaluated by quantitative reverse-transcription PCR. Methylation status was investigated by methylation-specific (MSP) PCR and bisulfate genomic sequencing (BGS). The prognostic significance of ZNF382 expression and promoter methylation was assessed in 105 cases of pediatric AML. The array data suggested that the ZNF382 promoter was hypermethylated in the AML cases examined. MSP PCR and BGS analysis revealed that ZNF382 was hypermethylated in leukemia cell lines. Furthermore, treatment with 5-aza-2'-deoxycytidine (5-Aza) upregulated ZNF382 expression in the selected leukemia cell lines. The aberrant methylation of ZNF382 was observed in 10% (2/20) of the control samples compared with 26.7% (28/105) of the AML samples. ZNF382 expression was significantly decreased in the 105 AML patients compared with the controls. Patients with ZNF382 methylation showed lower ZNF382 transcript levels compared with patients exhibiting no methylation. There were no significant differences in clinical characteristics or cytogenetic analysis between the patients with or without ZNF382 methylation. ZNF382 methylation correlated with minimal residual disease (MRD). Kaplan-Meier survival analysis revealed similar survival times in the samples with ZNF382 methylation, and multivariate analysis revealed that ZNF382 methylation was not an independent prognostic factor in pediatric AML. The epigenetic inactivation of ZNF382 by promoter hypermethylation can be observed in AML cell lines and pediatric AML samples. Therefore, our study suggests that ZNF382 may be considered a putative tumor suppressor gene in pediatric AML. However, further studies focusing on the mechanisms responsible for ZNF382 downregulation in pediatric leukemia are required.


Asunto(s)
Metilación de ADN , Proteínas de Unión al ADN/genética , Regulación hacia Abajo , Leucemia Mieloide/genética , Regiones Promotoras Genéticas/genética , Factores de Transcripción/genética , Enfermedad Aguda , Azacitidina/análogos & derivados , Azacitidina/farmacología , Línea Celular Tumoral , Niño , Decitabina , Inhibidores Enzimáticos/farmacología , Femenino , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Células HL-60 , Humanos , Células Jurkat , Células K562 , Estimación de Kaplan-Meier , Leucemia Mieloide/metabolismo , Masculino , Neoplasia Residual , Pronóstico , Modelos de Riesgos Proporcionales , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/estadística & datos numéricos , Células U937
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